Stimulation of Akt poly-ubiquitination and proteasomal degradation in P388D1 cells by 7-ketocholesterol and 25-hydroxycholesterol

Liu, June; Netherland, Courtney; Pickle, Theresa G.; Sinensky, Michael; Thewke, Douglas P.

doi:10.1016/j.abb.2009.05.004

Cited by 8 publications

(4 citation statements)

References 39 publications

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“…Protein ubiquitination is an important post‐translational modification that regulates various biological functions 27, 30. It has been reported that Akt undergoes K63 ubiquitination, which is a critical regulator of Akt phosphorylation 29, 30. Therefore, Akt ubiquitination (K63) was further measured in sublytic C5b‐9‐treated GMCs.…”

Section: Discussionmentioning

confidence: 99%

“…Protein ubiquitination is an important post‐translational modification regulating various biological events, such as cell proliferation and apoptosis 27–29. Many reports have confirmed that Akt undergoes lysine‐63 chain (K63) ubiquitination, which is necessary for Akt phosphorylation 29, 30. The process of ubiquitination involves three enzymes (E1–E3).…”

Section: Introductionmentioning

confidence: 99%

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Sublytic C5b‐9 complexes induce proliferative changes of glomerular mesangial cells in rat Thy‐1 nephritis through TRAF6‐mediated PI3K‐dependent Akt1 activation

Qiu

Zhang

Liu

et al. 2011

The Journal of Pathology

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The proliferation of glomerular mesangial cells (GMCs) and secretion of extracellular matrix (ECM) in rat Thy-1 nephritis (Thy-1N), resembling human mesangioproliferative glomerulonephritis (MsPGN), have been studied for many years, but the mechanisms, especially the role of signalling pathway activation and its regulation in GMCs triggered by sublytic C5b-9 complexes in Thy-1N rats remain largely unclear. In the study, the proliferation of GMCs and production of ECM as well as the role of PI3K/Akt and its regulation, both in GMCs induced by sublytic C5b-9 (in vitro) and in the renal tissues of rats with Thy-1N (in vivo), were determined and the results revealed that GMCs proliferation and ECM secretion, both in vitro and in vivo, were notably increased, and that PI3K/Akt1 activation and its regulation, such as TNF receptor-associated factor 6 (TRAF6)-mediated Akt1 ubiquitination and PI3K-dependent Akt1 phosphorylation, were involved in the process of Thy-1N induction. On the other hand, silence of the TRAF6, PI3K or Akt1 genes could obviously diminish the proliferative damages and urinary protein secretion of Thy-1N rats. Together, these data implicated that sublytic C5b-9 complexes in Thy-1N rats could promote GMCs proliferation and ECM production through TRAF6-mediated PI3K-dependent Akt1 activation, in which the ubiquitination and phosphorylation of the Akt1 signal molecule played an important role in the initiation and development of the proliferative changes in the rats with Thy-1N.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sublytic C5b‐9 complexes induce proliferative changes of glomerular mesangial cells in rat Thy‐1 nephritis through TRAF6‐mediated PI3K‐dependent Akt1 activation

Qiu

Zhang

Liu

et al. 2011

The Journal of Pathology

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“…This is prevented by Akt, which phosphorylates GSK-3. In turn, 25-HC degrades Akt [36], which would derepress GSK-3 and promote SREBP-2(M) degradation. Given that δ-tocotrienol has been shown to reduce Akt activity [37,38], and 25-HC and δ-tocotrienol act synergistically ( Figure 5B), could δ-tocotrienol influence the Akt/GSK-3/Fbw7 axis of SREBP-2(M) degradation?…”

Section: Tocotrienols Act By Degrading Mature Srebp-2mentioning

confidence: 99%

A key regulator of cholesterol homoeostasis, SREBP-2, can be targeted in prostate cancer cells with natural products

Krycer

Phan

Brown

2012

Biochemical Journal

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There is growing evidence showing that prostate cancer cells have perturbed cholesterol homoeostasis, accumulating cholesterol to promote cell growth. Consequently, cholesterol-lowering drugs such as statins are being evaluated in prostate cancer treatment. Furthermore, natural products such as betulin (from birch tree bark) and tocotrienol (a minor form of vitamin E) have been shown to lower cholesterol levels. Using these drugs and oxysterols, we have determined which aspects of cholesterol homoeostasis should be targeted in prostate cancer, e.g. cellular cholesterol levels are increased by the transcription factor SREBP-2 (sterol-regulatory-element-binding protein isoform 2), whereas LXR (liver X receptor) promotes cholesterol efflux. Whereas betulin exerted non-specific effects on cell viability, tocotrienols produced a strong direct correlation between SREBP-2 activity and cell viability. Mechanistically, tocotrienols lowered SREBP-2 activity by degrading mature SREBP-2 independently of the proteasome. In contrast, no correlation was seen between LXR activity and cell viability, implying that SREBP-2 is a better target than LXR for prostate cancer treatment. Lastly, androgen-dependent and -independent LNCaP cells were both sensitive to tocotrienols. Overall, this suggests that tocotrienols and other drugs targeting the SREBP-2 pathway are a potential therapeutic option for prostate cancer.

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“…This seems to depend on the particular in vitro model being investigated. It can induce endoplasmic reticulum (ER) stress [15] , stimulation of Akt [16] , cell proliferation through the epidermal growth factor receptor (EGFR) [17] and activation of the Toll-like receptor 4 (TLR4) [18] , to mention a few. The consensus in the published literature is that NFκB- mediated cytokine production is the main pathway responding to 7KCh-induced inflammation.…”

Section: Introductionmentioning

confidence: 99%

7-Ketocholesterol-Induced Inflammation Signals Mostly through the TLR4 Receptor Both In Vitro and In Vivo

et al. 2014

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The cholesterol oxide 7-ketocholesterol (7KCh) has been implicated in numerous age-related diseases such as atherosclerosis, Alzheimer's disease, Parkinson's disease, cancer and age-related macular degeneration. It is formed by the autooxidation of cholesterol and especially cholesterol-fatty acid esters found in lipoprotein deposits. This molecule causes complex and potent inflammatory responses in vitro and in vivo. It is suspected of causing chronic inflammation in tissues exposed to oxidized lipoprotein deposits. In this study we have examined the inflammatory pathways activated by 7KCh both in cultured ARPE19 cells and in vivo using 7KCh-containing implants inserted into the anterior chamber of the rat eye. Our results indicate that 7KCh-induced inflammation is mediated mostly though the TLR4 receptor with some cross-activation of EGFR-related pathways. The majority of the cytokine inductions seem to signal via the TRIF/TRAM side of the TLR4 receptor. The MyD88/TIRAP side only significantly effects IL-1β inductions. The 7KCh-induced inflammation also seems to involve a robust ER stress response. However, this response does not seem to involve a calcium efflux-mediated UPR. Instead the ER stress response seems to be mediated by yet identified kinases activated through the TLR4 receptor. Some of the kinases identified are the RSKs which seem to mediate the cytokine inductions and the cell death pathway but do not seem to be involved in the ER stress response.

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Stimulation of Akt poly-ubiquitination and proteasomal degradation in P388D1 cells by 7-ketocholesterol and 25-hydroxycholesterol

Cited by 8 publications

References 39 publications

Sublytic C5b‐9 complexes induce proliferative changes of glomerular mesangial cells in rat Thy‐1 nephritis through TRAF6‐mediated PI3K‐dependent Akt1 activation

Sublytic C5b‐9 complexes induce proliferative changes of glomerular mesangial cells in rat Thy‐1 nephritis through TRAF6‐mediated PI3K‐dependent Akt1 activation

A key regulator of cholesterol homoeostasis, SREBP-2, can be targeted in prostate cancer cells with natural products

7-Ketocholesterol-Induced Inflammation Signals Mostly through the TLR4 Receptor Both In Vitro and In Vivo

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